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© 2002 American Society for Clinical Oncology
Bisphosphonates and Tumor BurdenCancer Therapy and Research Center, Institute for Drug Development, University of Texas Health Science Center, San Antonio, TX THE ARTICLE BY Powles et al1 in this issue of the Journal of Clinical Oncology adds to the evidence that clodronate is a useful tool in the treatment of patients with advanced breast cancer. A number of animal and clinical studies in recent years have suggested that the bisphosphonates in general, and clodronate in particular, have the unanticipated benefit in patients with advanced breast cancer of not only reducing osteolysis and skeletal-related events2 but also decreasing tumor burden. This current work is the largest reported randomized controlled study to date of bisphosphonate use in patients with breast cancer, and provides three essential findings: (1) in patients with primary breast cancer treated with clodronate, there are fewer bone metastases during the treatment period for as long as the medication is maintained; (2) there is no significant effect on nonosseous metastases, in contrast to a report by Saarto et al,3 which suggested that there is a harmful effect; and (3) there is an improvement in overall survival in the patients treated with clodronate. A number of specific issues are raised by this current study. There was an absence of a significant effect on visceral metastases. Whether bisphosphonates have an effect on tumor burden at metastatic sites has been highly controversial over the past 5 years. Diel et al4 noted, in their patients, that there was a beneficial effect, whereas Saarto et al3 found the opposite. Most clinical oncologists would be surprised if there were a major effect on visceral metastases from drugs that target the osteoclast on nonbone metastases, and the experimental evidence in preclinical models would confirm this view. I suspect that the discordant findings in these two reports may be the result of insufficient sample sizes, although it remains possible that other issues, such as differences in methods of patient selection, are in part responsible. This point notwithstanding, the majority of clinical studies, together with the preclinical data,5 suggest that bisphosphonates cause a decrease in tumor burden in osseous metastatic sites. In terms of the duration of treatment, the patients studied by Powles showed a beneficial effect only while being treated and not after treatment was completed. This provides an argument for long-term bisphosphonate use in patients with metastatic breast cancer. The drugs are relatively harmless and inexpensive and have other beneficial effects such as preservation of bone mineral density.6,7 Thus, this current work suggests continued or long-term treatment may be desirable if the results could be confirmed in a larger randomized trial. What is also uncertain is whether there are beneficial effects on survival. It is very difficult to unravel the importance of metastases in different sites on patient survival, particularly if there is a beneficial effect on some and not on others. I would anticipate that a reduction in tumor burden in the bone marrow, combined with a reduction in osteolysis associated with bone metastasis, would improve patient survival provided sufficient patients were studied. There are other implications to be gleaned from this study. For example, when should treatment begin, and do patients come to harm if they are treated before metastases are apparent? This study would suggest not. Does clodronate have a special advantage over other bisphosphonates, and would the results of the trial apply to other malignancies such as renal cancer, lung cancer, prostate cancer, or myeloma? For myeloma, the answer is probably in the affirmative, although these other malignancies cause bone lesions in which there are differences from breast cancer metastasis to bone. Nevertheless, in all cases of osteolytic bone disease caused by cancer, osteoclastic bone resorption is a key element to the effects on bone,8 and the osteoclast must be regarded as a the prime cellular target for therapies. The mechanisms responsible for the bone effects in myeloma and prostate cancer are probably quite different. In myeloma, osteolysis predominates with very little bone formation response. Although the mediators responsible are almost certainly different in myeloma, osteoclast activation is the underlying bone cell event responsible for the skeletal effects, and bisphosphonates have been well demonstrated to have beneficial effects.9,10 On the other hand, in patients with metastatic prostate cancer, osteoblastic lesions predominate but a resorption element is also apparent as evidenced by increased bone resorption markers. Bisphosphonates are now being investigated extensively in patients with metastatic prostate cancer, and they may turn out to also hold a useful place in this disease. Does clodronate offer special advantages over other bisphosphonates? Clodronate is a bisphosphonate that does not contain nitrogen. It has a different mechanism of action from the nitrogen-containing bisphosphonates, which target specific enzymes in the mevalonate pathway.11-14 Clodronate causes osteoclast apoptosis and ultimately leads to impairment of bone resorption though this mechanism but does not inhibit farnesyl diphosphate synthase. It seems that the differences in mode of action between the bisphosphonates are not important with respect to their beneficial effects on bone metastasis. The main advantage of clodronate over other clinically used bisphosphonates is its oral availability and the fact that it has been so extensively studied. Other orally available bisphosphonates, such as alendronate and risedronate, have not been studied for this indication and should not be used if there is an alternative. Unfortunately, clodronate is not available in the United States, which means that American oncologists have no available approved oral bisphosphonate for this indication. This is indeed a shame, because the current study of Powles et al1 suggests that an orally active bisphosphonate clearly has beneficial effects in patients with breast cancer. An ongoing controversy, not addressed in this article, is whether bisphosphonates have direct effects on tumor cells or their effects are mediated by changes they cause in the bone microenvironment, making the skeleton a less hospitable site for tumor cells to grow and behave aggressively. Bone is a particularly favorable site for the growth of breast cancer cells, and they express parathyroid hormone related-peptide in this environment and grow profusely.15 We now understand that this is in part because of the production of bone growth factors in the bone marrow that enhance tumor cell production of parathyroid hormone related-peptide.16,17 There is also a growing body of evidence suggesting that bisphosphonates have direct effects on tumor cells, but the concentrations are high, much greater than expected at local sites in vivo.18-20 Thus, although there are still many questions regarding the use of bisphosphonates in patients with early and advanced breast cancer that remain unresolved, this work does improve our understanding of how, where, and for how long they should be used, and some of the benefits we can expect to see in our patients. For these reasons, the report of Powles et al1 is a major step forward in this area. REFERENCES
1. Powles T, Paterson S, Kanis JA, et al: Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20: 3219-3224, 2002
2. Hortobagyi GN, Theriault RL, Porter L, et al: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 335: 1785-1791, 1996
3. Saarto T, Blomqvist C, Birkkunen P, et al: Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 19: 10-17, 2001
4. Diel IJ, Solomayer E-F, Costa SD, et al: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339: 357-363, 1998
5. Sasaki A, Boyce BF, Wright KR, et al: Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res 55: 3551-3557, 1995
6. Powles T, McCloskey E, Paterson A, et al: Oral clodronate and reduction in loss of bone mineral density in women with operable primary breast cancer. J Natl Cancer Inst 90: 704-708, 1998 7. Powles TJ, Patterson AHG, Nevantaus A, et al: Adjuvant clodronate reduces the incidence of bone metastases in patients with primary operable breast cancer. Proc Am Soc Clin Oncol 17: 123a, 1998 (abstr 468) 8. Boyde A, Maconnachie E, Reid SA, et al: Scanning electron microscopy in bone pathology: Review of methods, potenial and applications. Scanning Electron Microscopy IV: 1537-1554, 1986
9. Berenson JR, Lichtenstein A, Porter L, et al: Efficacy of pamidronate in reducing skeletal events in patients with advanced myeloma. N Engl J Med 334: 488-493, 1996 10. McCloskey EV, MacLennan ICM, Drayson M, et al: A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. Br J Haematol 100: 317-325, 1998[CrossRef][Medline] 11. Rogers MJ, Watts DJ, Russell RG: Overview of bisphosphonates. Cancer 80: 1652-1660, 1997 (suppl 8)[CrossRef][Medline] 12. Luckman SP, Hughes DE, Coxon FP, et al: J Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including rats. J Bone Miner Res 13: 581-589, 1998[CrossRef][Medline] 13. Van Beek E, Pieterman E, Cohen L, et al: Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun 264: 108-111, 1999[CrossRef][Medline]
14. Reszka AA, Halasy-Nagy JM, Masarachia PJ, et al: Bisphosphonates act directly on the osteoclast to induce cleavage of mst1 kinase during aptosis: A link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase. J Biol Chem 274: 34967-34973, 1999
15. Powell GJ, Southby J, Danks JA, et al: Localization of parathyroid hormone-related protein in breast cancer metastases: Increased incidence in bone compared with other sites. Cancer Res 51: 3059-3061, 1991 16. Guise TA, Yin JJ, Taylor SD, et al: Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest 98: 1544-1549, 1996[Medline] 17. Yin JJ, Chirgwin JM, Dallas M, et al: Blockade of TGFß signaling inhibits parathyroid hormone-related protein (PTH-rP) secretion by breast cancer cells and the development of bone metastasis. J Clin Invest 103: 197-206, 1999[Medline] 18. Rogers MJ, Watts DJ, Russell RGG: Overview of bisphosphonates. Cancer 80: 1652-1660, 1997[CrossRef][Medline] 19. Shipman CM, Rogers MJ, Apperley JF, et al: Bisphosphonates induce apoptosis in human myeloma cell lines: A novel anti-tumour activity. Br J Haematol 98: 665-672, 1997[CrossRef][Medline] 20. Aparicio A, Gardner A, Tu Y, et al: In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia 12: 220-229, 1998[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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